This invention relates to a method of inhibiting parasitic activity by inhibiting the biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor of the parasite. More particularly, the invention relates to the inhibition of parasitic activity by incorporating into the GPI anchor of the parasite an oxy-substituted fatty acid analog in place of myristate.
Glycosyl phosphatidylinositols (GPIs) anchor diverse proteins to the plasma membranes of organisms ranging from the yeasts to mammals. See, e.g., the review article by Low, Biochem. J. 244, 1-13 (1987). The most completely characterized GPI anchor is that of the variant surface glycoprotein (VSG) of the parasitic protozoan Trypanosoma brucei. See, e.g., the research article by Ferguson et al., Science 239, 753-759 (1988), for the complete primary structure of the GPI anchor of VSG variant 117. This parasite, in common with other African trypanosomes, evades the mammalian immune system by antigenic variation in which individual genes encoding immunologically distinct VSGs form a dense surface coat. The VSG coat acts as a macromolecular diffusion barrier which protects the parasite from lytic host-serum components.
Trypanosoma brucei is a protozoan bloodstream parasite responsible for African sleeping sickness which has a devastating effect on human health and on livestock production. Consequently, methods of inhibiting the activity of this and related protoazoan parasites would have significant importance to medical science and for the development of therapeutic intervention to parasitic diseases.